Transdermal drug delivery, delivery of drugs through the skin, provides many advantages. Primarily, it is a comfortable, convenient and non-invasive way of administering drugs. Drugs delivered transdermally directly enter subdermal blood vessels, and are transported to the target site via by-passing the first-pass liver metabolism and decomposition. This method allows for high drug bioavailability. The system requires a relatively small amount of drug and can be an effective method for sustained drug delivery, allowing for a reduced frequency of administration. Moreover, such a means of delivery provides uninterrupted therapy and a higher degree of control over drug concentrations in the blood. These characteristics help avoid side effects caused by temporarily high blood concentrations of drugs which accompany administration of oral dosage forms and injections.
The outer layer of the skin called the stratum corneum, however, forms a barrier to drug absorption for almost all compounds and often prevents the delivery of an effective amount of the drug. Due to the hydrophobic nature of the stratum corneum, absorption of the hydrophilic salts of drugs is especially difficult. Large molecules and extremely hydrophobic drugs also have difficulty being absorbed through the skin.
Chemical enhancers are commonly used to overcome the stratum corneum barrier. These enhancers, however, can introduce side effects such as skin irritation and formulation incompatibility and often still can not increase drug absorption sufficiently to meet the drug's therapeutic dose requirement.
Additionally, physical means are a common method used to overcome the stratum corneum barrier function. These means include iontophoresis, electroporation, sonophoresis, and skin micro abrasion.
U.S. Pat. No. 4,409,206 discloses a preparation in the form of a polyacrylate film with an amorphous active pharmaceutical ingredient embedded therein.
United States Publication No. 2005/0064022 describes a terazosin transdermal device and methods of use. The publication discloses the preparation of terazosin in amorphous form by spray drying, roller drying and freeze drying prior to incorporation into the transdermal delivery device. More specifically, the publication discloses a transdermal therapeutic system for the administration of amorphous terazosin to the skin, comprising a backing layer, a pressure-sensitive adhesive reservoir layer and/or a matrix layer, and optionally a removable protective layer.
United States Publication No. 2005/0175678 is directed to a polymer matrix suitable for the transdermal administration of rotigotine and a method of preparing the same. The polymer matrix contains a supersaturated amount of a rotigotine base such that the portion of the rotigotine that is not dissolved in the matrix polymeric adhesive is dispersed in the adhesive matrix as amorphous particles. The publication further discloses that the matrix adhesive may be a component of a system for transdermal administration of rotigotine, wherein the system can have components such as a protective layer, a backing layer, further polymeric adhesive layers, and/or a membrane which controls the release of the rotigotine.
U.S. Pat. No. 6,902,741 is directed to a transdermal system which includes a sex hormone-containing adhesive matrix, containing inclusions of sex hormone in a hydrophilic non-crosslinked polymer. The active sex hormone contained in the inclusions is preferably amorphous to an extent of more than 50% by weight of the active substance. The active sex hormone-containing laminate is characterized in that the active sex hormone inclusions are contained in the adhesive matrix in dissolved or dispersed form and that the active sex hormone inclusions are pre-prepared prior to incorporation to the adhesive matrix. Thus the process requires a step of pre-preparation of the active hormone inclusion, followed by another step of incorporating the inclusions to an adhesive matrix polymer solution.
Various methods of manufacturing transdermal systems in which the drug is supersaturated are known. U.S. Pat. Nos. 4,409,206, 4,490,322, 4,797,284, 4,880,633, 5,352,457 5,869,089, 5,906,830, 6,153,216, 6,156,335, and 6,623,763 describe methods of manufacturing transdermal systems. U.S. Pat. No. 4,490,332 discloses a method of manufacturing a polyacrylate film for long term transdermal administration by forming a solution of a pharmaceutical and a freeze-dried latex polyacrylate copolymer in a solvent. U.S. Pat. No. 5,906,830 discloses a method of manufacturing a supersaturated transdermal system comprising heating a mixture of undissolved drug and reservoir matrix material to a predetermined temperature, followed by cooling.
Scopolamine is a difficult molecule to administer transdermally as the molecule recrystallizes in both laminate and patch delivery systems. As this recrystallization occurs, the delivery rate is reduced. Several U.S. patents (U.S. Pat. Nos. 4,832,953, 5,662,928, 6,569,448, 6,238,700) describe an annealing method to anneal laminates and patches for removal or prevention of formation of crystalline scopolamine or their hydrates. These processes are tedious, complex and costly.
Oxybutynin is also a troublesome molecule for transdermal delivery. U.S. Pat. No. 5,164,190 discloses transdermal administration of hydrophobic drugs via a diffusion mechanism in which the drug is dissolved in a carrier at concentrations between 20% and 80% of saturation concentration. U.S. Patent Application No. 2004/0057985 discloses a transdermal system wherein a matrix layer comprises two phases which are immiscible with each other, namely an inner phase and an outer phase.
U.S. Patent Application No. 2004/0081683 discloses a transdermal system containing a self-adhesive matrix consisting of an adhesive polymer and an amine functional drug including oxybutynin and is free of particles that absorb salts of amine functional drugs.
Naltrexone is poorly absorbed through the skin and therefore prodrugs have been developed to enhance the skin absorption. The absorption rate of the prodrugs, however, is still insufficient to achieve therapeutic dosages.
Testosterone is also poorly absorbed from the skin even in the presence of a high level of enhancers.
Although the required therapeutic dose is low, the transdermal delivery rate of crystalline estradiol often can not achieve the therapeutic level.
Thus there remains a need for a stable transdermal system which can improve the absorption rate through the skin for various therapeutic agents.